Mitogen‐activated protein kinase p38 target regenerating islet‐derived 3γ expression is upregulated in cardiac inflammatory response in the rat heart

Abstract

Regenerating islet‐derived 3γ (Reg3γ) is a multifunctional protein, associated with various tissue injuries and inflammatory states. Since chronic inflammation is characteristics also for heart failure, the aim of this study was to characterize Reg3γ expression in cardiac inflammatory conditions. Reg3γ expression was studied in experimental rat models of myocardial infarction (MI) and pressure overload in vivo. For cell culture studies neonatal rat cardiac myocytes (NRCMs) were used. In addition, adenovirus‐mediated gene transfer of upstream mitogen‐activated protein kinase (MAPK) kinase 3b and p38α MAPK in vivo and in vitro was performed. Reg3γ mRNA (12.8‐fold, P < 0.01) and protein (5.8‐fold, P < 0.001) levels were upregulated during the postinfarction remodeling at day 1 after MI, and angiotensin II (Ang II) markedly increased Reg3γ mRNA levels from 6 h to 2 weeks. Immunohistochemistry revealed that the Ang II‐induced expression of Reg3γ was localized into the cardiac fibroblasts and myofibroblasts of the proliferating connective tissue in the heart. Stretching and treatments with endothelin‐1, lipopolysaccharide (LPS), and fibroblast growth factor‐1 increased Reg3γ mRNA levels in NRCMs. SB203580, a selective p38 MAPK inhibitor, markedly attenuated LPS and mechanical stretch‐induced upregulation of Reg3γ gene expression. Moreover, combined overexpression of MKK3bE and WT p38α increased Reg3γ gene expression in cultured cardiomyocytes in vitro and in the rat heart in vivo. Our study shows that cardiac stress activates Reg3γ expression and p38 MAPK is an upstream regulator of Reg3γ gene expression in heart. Altogether our data suggest Reg3γ is associated with cardiac inflammatory signaling.

Mechanical stretch induced transcriptomic profiles in cardiac myocytes

“…Our analysis identified many novel mechanical stretch responsive genes in cardiomyocytes. For example, we and others have subsequently revealed activating transcription factor 3 28 , bone morphogenetic protein 2 29 , regenerating islet-derived 3γ 30 , dyxin/LMCD1 31 , 32 , Fn14 (or TNFrsf12a) 33 , 34 , Wdr12 35 , myeloid leukemia factor-1 36 , Myomasp/LRRC39 37 and phosphatase and actin regulator 1 (PHACTR1) 38 to be a part of stretch activated hypertrophic gene program in NRVMs. We validated the reliability of our data by undertaking a DNA microarray analysis; this identified well-established changes of hypertrophic gene expression programme in mechanically stretched cardiomyocytes.…”

P. gingivalis Lipopolysaccharide Stimulates the Upregulated Expression of the Pancreatic Cancer-Related Genes Regenerating Islet-Derived 3 A/G in Mouse Pancreas

“…Recently, the P. gingivalis membrane, which is supposed to contain LPS, was reported to activate both NF-kB and MAPK [ 28 ]. LPS derived from E. coli induces the upregulated expression of Reg3G via the p38 MAPK pathway [ 29 ]. These pathways may be involved in the upregulation of Reg3A and G by PG-LPS stimulation.…”

p38 MAPK Pathway in the Heart: New Insights in Health and Disease

“…p38 has also been linked to cardiac inflammation through its promotion of the expression of regenerating islet-derived 3γ (Reg3γ), a protein associated with cardiac inflammatory signaling [ 70 ]. Moreover, treatment with the anti-inflammatory compound gamboge protects against infarction-induced inflammation by targeting the NF-κB–p38 pathway [ 71 ].…”